180 infants were randomized to receive preterm formula whenever there was insufficient maternal breast milk. The other group of 180 received pasteurized donor breast milk whenever there was not enough breast milk. Infants received their assigned supplement until 90 days or discharge, whichever occurred first, and continued to get the assigned diet if they were back-transferred to a level 2 nursery before going home.

The study was well-designed and carried out, but unfortunately vastly underpowered. All NICUs now try and give mother’s milk to the babies, which is always the first choice, so nearly 30% of the babies in each group never received a supplement, which makes them uninformative for the primary outcome, which was Bayley Testing at 18 months of age.

Of those that did receive a supplement, the median proportion of total enteral feeds for each infant consumed as mother’s milk was 58.4% [IQR, 13.6%-96.0%] for the donor milk group vs 63.3% [IQR, 9.6%-97.2%] for the formula group. So in other words some of the babies received as little as 3% of their feeds as the assigned diet, and about half received around 40% or more.

I think its fairly obvious that receiving only a tiny proportion of your feeds as formula is highly unlikely to have a measurable effect on developmental delay. The only babies that you might think could possibly have an effect would be those with a significant percentage of their milk being donor milk, rather than formula.

As you can see from those figures above, half of those who did get the assigned diet received more than 40% of their feeds as something other than mother’s milk. We could guess that 40% might be enough to show an effect if there was one, if we use that as the threshold, there were only approximately 60 babies per group, of whom 92% had follow up, or about 55. The power of detecting an effect on development with only 55 per group is rather low.

I understand the need to do intention to treat analysis, but in a study such as this, where it was expected that 30% of the babies would never receive the assigned intervention, (and not because of protocol deviations, but because the mother is able to produce enough milk) you could easily argue that the main analysis should be among those who did actually need a supplement.

This is not the same as, for example a study comparing planned vaginal breech delivery to planned cesarean, where the clinical question is “what should I plan for the delivery of this baby?” The clinical question here was, “if we need to supplement, what should we do it with?” and it is a question that can be posed when you get to the point of there not being enough breast milk. Enrolling mothers and getting consent could be done soon after birth, but actually randomizing and collecting data could be done only when the baby needs a supplement, which would increase the power of the study.

As it is, there are a limited number of babies in the trial who are informative for the outcome, which means that a substantial benefit (or harm) of supplementation with donor milk, on the primary outcome, could have been missed.

Secondary outcomes are also underpowered, but even with this lack of power, there was a significant reduction in NEC, from 6.6% (stage 2 or more) with formula supplementation to 1.7%, with donor milk as a supplement. Other outcomes including late onset sepsis were not different between groups.

There are all sorts of goodies in human milk for preterm babies, and this study confirms that NEC is less frequent when you supplement with donor milk compared to preterm formula. It wouldn’t be surprising that the impact on NEC required less cow’s milk than an impact on developmental delay, so a large relative difference between groups, for this outcome, is biologically plausible.

Also of note, most of the babies in this study were exposed to cow’s milk protein. Both in the formula group, but also in the breast milk groups, as milk was fortified with cow’s milk based breast milk fortifier, even if the baby only received their own mother’s milk.

The conclusions state the following:

Results from the present study suggest no advantage of feeding nutrient-enriched donor milk compared with preterm formula, as a supplement to mother’s milk, on neurodevelopment of VLBW infants at 18 months’ corrected age.

But that isn’t quite right, the study suggests no advantage of a strategy of being ready to receive nutrient enriched donor milk if needed, compared to a strategy of getting formula if needed. That comparison showed no overall impact on Bayley scores, but did show a benefit in terms of NEC.

The results are consistent with a substantial effect of breast milk on neuro-development, (as well as being consistent with no effect or with a negative effect).

To be honest, I don’t think we need to do more studies like this, concentrating on helping mothers to express their milk, and when necessary supplementing with donor milk, should be the standard of care. This study confirms the benefits in terms of NEC, and didn’t show any downside of breast milk supply to preterm babies.

3 Responses to Breast milk doesn’t make you smarter?

This is really a shocking title which doesn’t reflect the message given in your review sir, the study used only Bayley score at 18 months of age and as you know low scores on the Bayley at 18 months do not equal cognitive impairment and in turn it is not a good indicator of future cognitive skills, in other words we can’t use it to decide how smart babies will be. So using the study results as an indicator of how smart babies will be by using different ways of nutrition is really shocking at least in my modest opinion.
I believe the study only indicates that using preterm formula doesn’t make babies at increased risk in terms of neuro developmental delay in comparison to supplemented donor human milk which again is not an indicator if any of the babies will be smarter or not.
My concern is the abuse of the title to push doctors to use more formula on the expense of breast milk especially that it is under a prestigious name as yours

I would welcome the acknowledgement both as an Infant Feeding Specialist and a mother of two prem babies, that fortifier is basically formula. It contains non-species specific protein. If the ‘exclusively’ mother’s breastmilk fed infants had fortifier added to the milk it is not surprising surely that there is a limited difference in outcomes between the two groups. This is also a major flaw of other recent and high profile studies seeking to establish feeding recommendations for premature infants, as fortified breastmilk is classed as exclusively human breastmilk fed.

There is some truth in what you say, breast milk alone cannot meet all of the nutritional requirements of very preterm babies (even in extremely large volumes there would not be enough phosphorus), so fortification is required, all the fortifiers available in Canada and Europe are based on Cow’s milk. The only alternative is the human milk based fortifier available in the US, which is shockingly expensive, and so far has not been proven to lead to better outcomes than Cow’s milk based fortifiers.
As for the evidence regarding long-term outcomes (which this post was about) there is no evidence of a negative (or positive) impact of fortifying breat milk with Cow’s milk derived protein. But there is evidence that optimal nutritional intakes have an impact on developmental outcomes.
Exclusive breastmilk feeding, even when fortified with Cow’s milk derived fortifiers does seem to reduce the incidence of NEC, and possibly of late-onset sepsis (though that evidence is more shaky). Of course you could call that “exclusive feeding with fortified breastmilk” but usually fortification is discontinued prior to discharge so that wouldn’t be accurate either. I think as long as the methods sections describe exactly what they mean by the term (which often includes an allowable small percentage of artificial formula rather than 100% breastmilk) I don’t think it is really a big issue.